Oxytocin with N5,N5-dimethylglutamine and N4,N4-dimethylasparagine in the 4 and 5 positions: synthesis,pharmacological properties and mass spectral analysis

The analog of oxytocin [4-(N⁵,N⁵-dimethylglutamine), 5-(N⁴,N⁴-dimethylasparagine)]-oxytocin was synthesized and its structure was fully characterized by liquid secondary mass ion spectroscopy. The analog was found to be almost inactive in the uterotonic, anti-diuretic, pressor and milk ejection assays.     

Metabolism studies of N,N-Dimethylformamide

Summary In acute 2-h studies male and female rats were exposed to N,N-dimethylformamide concentrations of 209, 87, and 104 ppm with or without anoral dose of ethanol (2.0 g ethanol/kg) prior to inhalation.In a subacute study (2 h/day on 5 consecutive days) with or without an oral administration of ethanol (2.0 g ethanol/kg) before starting the test, the N,N-dimethylformamide concentration was approx. 200 ppm.Acute inhalation studies were performed on male dogs with N,N-dimethylformamide concentrations of 210–240 ppm and oral dose of ethanol (2.0 g ethanol/kg) immediately after or before the exposure.In addition, 4 persons were exposed to N,N-dimethylformamide concentrations of 50–80 ppm for 2 h, with or without preceding oral ethanol administration (19 g ethanol/person).The metabolic behavior of N,N-dimethylformamide and its metabolites (N-methylformamide, formamide) in blood and urine under the influence of ethanol was investigated.Additionally, in the subacute study on rats as well as in the acute studies on persons, the ethanol and acetaldehyde concentration was also determined.A delayed catabolisation of N,N-dimethylformamide was observed in the organism of rats and dogs after the oral administration of 2.0 g ethanol/kg prior to inhalation. This was confirmed by the elevated N,N-dimethylformamide concentration in the blood which decreased very slowly after exposure. After the administration of ethanol, N-methylformamide was not immediately detectable at the end of the inhalation period, but it was only found after a certain time lapse.A small oral dose of 0.2 g ethanol/kg body weight on rats prior to inhalation, did not influence the metabolism of N,N-dimethylformamide.During repeated exposure and daily pretreatment with ethanol, the metabolisation of N,N-dimethylformamide was also inhibited. However, the metabolisation of ethanol seemed also to be influenced by N,N-dimethylformamide.After exposure and preceding administration of ethanol no increase of the N,N-dimethylformamide level in the blood of persons could be found. However, a comparatively lower N-methylformamide concentration in the blood damage of the membrane of the endoplasmic reticulum would be imaginable.After acute ethanol intoxication Rubin et al. (1970) observed a decrease in the cytochrome P-450 activity in rats, which influences the electron transfer system and thus causes a dysfunction of the oxidation chain in the metabolism of foreign substances.Cinti et al. (1973) reported on the interference of high ethanol concentrations with the binding of drug substrates to cytochrome P-450.During repeated DMF exposure to rats, a slight inhibition of the ethanol oxidation was observed. This permits the supposition that it is only a question of concentration as to whether the inhibited metabolisation of the one substance is greater than that of the other.Further experimental studies are planned to establish whether DMF or MF like some other amides (N-butyramide, isobutyramide; Lester, 1970) are able to inhibit ethanol- or acetaldehyde-dehydrogenase.The occasionally observed intolerance reaction in employees exposed to DMF indicates an inhibition of the ethanol oxidation. However, in order to demonstrate this effect, significantly higher DMF exposures than we used in our study on persons are probably necessary. No influence can be expected on the metabolisation of ethanol in man at a DMF-exposure within the MAC range.     

二甲基甲酰胺生殖毒性研究进展

二甲基甲酰胺(DMF)是一种在现代工业中广泛应用的有机化合物.随着DMF使用量的逐年增加,其毒性引起人们的广泛关注.动物研究和流行病学调查显示,DMF对人和动物的生殖功能均有一定程度的损害作用.该文介绍了DMF对动物及职业人群生殖功能的影响,并提出了今后的主要研究方向.     

Metabolism studies of N,N-dimethylformamide

Summary In acute and subacute inhalation studies rats and dogs were exposed to N,N-dimethylformamide. In addition dogs were subjected to subchronic inhalation tests.The rats were subjected to N,N-dimethylformamide concentrations of 21, 146 or 2005 ppm during the 3-hr trial. During the 6-hr exposure they were subjected to 29 or 170 ppm.In the case of repeated exposures on rats the average concentration was 350 ppm.In the 6-hr test dogs were exposed to 20, 32, 143 or 172 ppm. In the 5-day test (6 hrs/day) they were exposed to 23 or 59 ppm, and in the 4-week test (6 hrs/day) the concentration was 20 ppm (MAC).The metabolisation of N,N-dimethylformamide was studied in rats and dogs. Methods for the analytical determination of the unchanged active substance and its metabolites (N-methylformamide and formamide) in blood and urine were developed.In addition to the already known metabolite N-methylformamide, a further metabolite, formamide, was found in the urine of rats and dogs. The elimination rate of N-methylformamide and formamide differed in dogs and rats. The elimination rate in dogs was much slower. In the group of dogs subjected to repeated inhalation of 59 ppm an accumulation of N-methylformamide was determined in the blood and urine. In the case of rats exposed to substantially higher subacute N,N-dimethylformamide concentration (350 ppm) this phenomenon was not observed.In the MAC-range (20 ppm) the dogs of the subacute and subchronic group showed no signs of accumulation.The results of the liver and kidney function studies in dogs exposed to 20 ppm N,N-dimethylformamide for 4 weeks were normal.     

同时测定工作场所空气中二甲基甲酰胺和二甲基乙酰胺的气相色谱质谱联用测定法

目的建立工作场所空气中二甲基甲酰胺（DMF）和二甲基乙酰胺（DMA）的气相色谱质谱联用测定法。方法采用多孔玻板吸收管采集,经DB-5MS毛细管色谱柱分离后气相色谱质谱联用仪测定。结果该方法 DMF和DMA的分离效果好,检出限分别为1.2和1.1μg/ml;方法的重现性好,相对标准偏差分别为1.6%-3.1%和1.8%-3.5%;平均加标回收率分别为94.2%-102.5%和92.9%-104.4%。结论该方法精确、稳定、灵敏度高,适用于工作场所空气中DMF和DMA的同时测定。     

毛细管气相色谱法同时测定工作场所空气中二甲基甲酰胺及二甲基乙酰胺

目的:建立毛细管色谱法同时检测作业场所空气中二甲基甲酰胺和二甲基乙酰胺的测定方法。方法:采用强极性毛细管色谱柱分离,FID检测器检测,柱温采用程序升温,氮气线流速3.5 ml/min。结果:线性关系良好,最低检出限。结论:方法适合测定作业场所空气中二甲基甲酰胺和二甲基乙酰胺的同时测定。     

Influence of heliox, oxygen, and N2O-O2 breathing on N2 bubbles in adipose tissue

Bubbles in rat adipose tissue were studied at 1 bar after decompression from an exposure to air at 3.3 bars (absolute) for 4 h. During air breathing the bubbles grew throughout the observation period. During heliox (80:20) breathing they shrank and eventually disappeared from view. If the breathing gas was changed from heliox back to air or to N2O-O2 (80:20) while the bubbles still had an appreciable size, they started growing again. If the change to N2O was done after or a few minutes before a bubble disappeared from view, it did not reappear. During breathing of 100% O2, most bubbles containing N2 initially grew and then maintained their size for a while before diminishing. However, some bubbles did not start shrinking during the 2-3-h observation period. The relevance of the findings to heliox treatment of CNS decompression sickness after air dives is discussed.     

Monitoring for N,N-dimethylformamide and N,N-dimethylacetamide with a diffusive sampler using distilled water as an absorbent

To obtain an appropriate sampling method for evaluating individual workers' exposure concentrations to chemicals highly soluble in water, the suitability of LiPS (liquid passive sampler) as diffusive sampler was examined. Although adsorbed chemical substances with activated carbon felt being used as the adsorbent must be desorbed in such samplers, this process can be omitted by using liquid as the absorbent. This kind of simplification can be utilized for water-soluble solvents such as N,N-dimethylformamide (DMF) and N,N-dimethylacetamide (DMAC). In laboratory experiments DMF and DMAC levels determined by this method were sufficiently correlated with exposure concentrations, exposure duration, and cumulative exposure levels. The sampling rates for DMF and DMAC obtained from these results were 0.50 and 0.43 mL/min, respectively, and the theoretical sampling rate for DMF obtained using Fick's diffusion formula was consistent with the experimental value. The effects of relative humidity, wind velocity, and temperature on the measured values were negligible within the range expected in a practical industrial environment. In a field survey the exposure concentrations for 38 workers handling DMF in the process of manufacturing spandex fiber and polyurethane gloves were determined both by this method and by the National Institute of Occupational Safety and Health (NIOSH) method, in which silica gel tubes are used. The DMF concentrations detected by the two methods were comparable (Y = 0.912X, correlation coefficient: 0.932). This LiPS method proved to be useful in determining the concentrations of DMF and DMAC to which workers were exposed.